Influenza A virus depends on the host cell machinery for its replication. Recognition ofthe virus by the host triggers a complex signaling cascade that results in the expression of numerous interferon (IFN)-simulated genes that respond to the virus and interfere with its life cycle. As an ancient antiviral defense mechanism, the innate immune response is a collection of functionally distinct subsystems that have evolved to counter infection by viruses. The influenza A virus, however, can bring about measures that subvert many components ofthe host innate immune response to infection. Differences in the genes relevant to the virus life cycle or immunity, from genetic variations or epigenetic factors, can contribute to host resilience. Many aspects ofthe virus-host interaction have not been described fully. Here, we will conduct a cohort study to determine whether mutation of genes encoding intermediates in signaling pathways and networks host factors identified by our 'omics' approach for which a plausible biological mechanism of action is found influences the virus life cycle. We will discover rare and disruptive variants in human genes required during virus replication or for host cell modifiers of infection relevant to the virus life cycle or immunity by targeted capture and high-throughput resequencing ofthe selected genes across individuals. We will map and quantify expression quantitative trait loci by high-throughput sequencing of cDNA libraries and produce genome-wide maps of chromatin accessibility to link genetic variation to changes in gene regulation and molecular phenotype. We will elucidate assess the impact ofthe predicted function-altering changes in host factors required for virus replication and innate immune defense to understand the mechanisms by which they affect the steps in the influenza A virus life cycle. We will follow the extant men over a subsequent season of influenza prospectively to associate changes in molecular phenotypes with changes in molecular and cellular processes and disease-related phenotype. With this approach, we anticipate finding novel cellular proteins required during virus replication, new host cell modifiers of infection, and their functional importance in restriction of infection that will provide valuable insights into the biological basis of disease.